Chapter 3 - Behavioral Outcome Measures for the Assessment of Sensorimotor Function in Animal Models of Movement Disorders

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Animal models have and continue to contribute to our understanding of the neurobiology many types of disorders. In movement disorders such as Parkinson's disease (PD), animal models have directly led to various therapeutic treatments such as deep brain stimulation. To facilitate the development of potential therapeutics, sensitive and reliable outcome measures in animal models are necessary to maximize their benefit. In this chapter, behavioral outcome measures, sensitive to varying degrees of sensorimotor dysfunction, are reviewed in rats and mice.

Introduction

The relationship between dopamine (DA) and movement has been studied in depth since the discovery of DA in the brain during the late 1950s and its association with the disorder Parkinson's disease (PD) soon thereafter. In PD, DA neurons in the substantia nigra progressively degenerate leading to motor abnormalities including resting tremor, bradykinesia, rigidity, and gait disturbances. A number of neurotoxins have been used to model the loss of nigrostriatal DA neurons seen in PD, the most extensively studied model being the 6-hydroxydopamine (6-OHDA) rat model. More recently, the discovery of genetic forms of PD has led to a new generation of novel genetic mouse models with the most detailed behavioral characterization performed in mice that overexpress the presynaptic protein alpha synuclein. In both models sensorimotor tests that are sensitive to dysfunction and loss of nigrostriatal DA neurons have been developed and are important tools in providing endpoint measures for preclinical testing of potential therapeutic treatments for PD. Although the tests described in this chapter have been used in models of PD, they are also applicable to other types of movement disorders such as stroke and spinal cord injury (Schallert et al., 2000).

Section snippets

Sensorimotor Tests for Unilateral 6-OHDA Rat

The toxin 6-OHDA is widely used to create animal models of PD (Kostrzewa and Jacobwitz, 1974, Schallert and Wilcox, 1985, Ungerstedt, 1968, Ungerstedt, 1971). 6-OHDA does not cross the blood–brain barrier and therefore is injected directly into the substantia nigra. Once in the cell, 6-OHDA forms cytotoxic products like hydrogen peroxide (Heikkila and Cohen, 1971), superoxide, and hydroxy radicals (Cohen and Heikkila, 1974, Heikkila and Cohen, 1973), leading to cell death.

Rats with unilateral

Sensorimotor Tests for Genetic Mouse Models

Within the past decade several genetic mutations causing rare familial cases of PD have been identified. Mutations in the presynaptic protein alpha synuclein were some of the first mutations to be described (Chartier-Harlin et al., 2004, Kruger et al., 1998, Polymeropoulos et al., 1997, Singleton et al., 2003). Soon after this, genetic mice carrying similar mutations were generated. In addition to mice with mutations associated with familial forms of PD, there have also been mice generated that

Acknowledgements

This work was funded by American Parkinson Disease Association and the Chen Family.

References (50)

  • D.A. Kozlowski et al.

    Delivery of a GDNF gene into the substantia nigra after a progressive 6-OHDA lesion maintains functional nigrostriatal connections

    Exp. Neurol.

    (2000)
  • R. Reliene et al.

    Effects of antioxidants on cancer prevention and neuromotor deficits in ATM deficient mice

    Food Chem. Toxicol.

    (2008)
  • T. Schallert et al.

    ‘Disengage’ sensorimotor deficit following apparent recovery from unilateral dopamine depletion

    Behav. Brain Res.

    (1988)
  • T. Schallert et al.

    Tactile extinction: Distinguishing between sensorimotor and motor asymmetries in rats with unilateral nigrostriatal damage

    Pharmacol. Biochem. Behav.

    (1982)
  • T. Schallert et al.

    Posture-independent sensorimotor analysis of inter-hemispheric receptor asymmetries in neostriatum

    Pharmacol. Biochem. Behav.

    (1983)
  • T. Schallert et al.

    CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury

    Neuropharmacology

    (2000)
  • M. Sedelis et al.

    Behavioral phenotyping of the MPTP mouse model of Parkinson's disease

    Behav. Brain Res.

    (2001)
  • M.S. Szczypka et al.

    Dopamine production in the caudate putamen restores feeding in dopamine-deficient mice

    Neuron

    (2001)
  • J.L. Tillerson et al.

    Detection of behavioral impairments correlated to neurochemical deficits in mice treated with moderate doses of 1 methyl-4-phenyl 1,2,3,6-tetrahydropyridine

    Exp. Neurol.

    (2002)
  • U. Ungerstedt

    6-Hydroxy-dopamine induced degeneration of central monoamine neurons

    Eur. J. Pharmacol.

    (1968)
  • M. Upchurch et al.

    A behavior analysis of the offspring of “haloperidol-sensitive” and “haloperidol-resistant” gerbils

    Behav. Neural. Biol.

    (1983)
  • I.Q. Whishaw

    Loss of the innate cortical engram for action patterns used in skilled reaching and the development of behavioral compensation following motor cortex lesions in the rat

    Neuropharmacology

    (2000)
  • M. Yang et al.

    Neural stem cells spontaneously express dopaminergic traits after transplantation into the intact or 6-hydroxydopamine-lesioned rat

    Exp. Neurol.

    (2002)
  • J. Broida et al.

    Strain-typical patterns of pregnancy-induced nestbuilding in mice: Maternal and experiential influences

    Physiol. Behav.

    (1982)
  • B. Connor et al.

    Differential effects of glial cell line-derived neurotrophic factor (GDNF) in the striatum and substantia nigra of the aged Parkinsonian rat

    Gene Ther.

    (1999)
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